The Japanese archipelago extends from a subtropical zone to a temperate zone and has a warm climate high in humidity, which is liable to facilitate propagation of fungi such as molds. In addition, due to westernization of clothes, people are now accustomed to wearing shoes on feet. Accordingly, afoot serves as a favorable environment for the propagation of the fungi, leading to mycotic skin diseases that are serious social issues nowadays. Of those, onychomycosis has a low complete cure rate and high relapsing and reinfection rates. Therefore, an effective therapy has been demanded.
Conventionally, treatments mainly using tolnaftate formulations have been conducted on such diseases. In recent years, imidazole-based antifungal agents, such as bifonazole and itraconazole, are mainly used.
As the imidazole-based antifungal agents, there are commercially available imidazole-based antifungal agents such as those represented by the general formula (1) described below, specifically, luliconazole represented by the structural formula (1) below and lanoconazole represented by the structural formula (2) below. The above-mentioned luliconazole is currently the newest imidazole-based antifungal agent, and a commercially available product called “Lulicon” (registered trademark) is also present (e.g., see Patent Document 1 and Patent Document 2).
The compounds each represented by the general formula (1) have a wide antifungal spectrum, in particular, remarkable antifungal activity against dermatophytes. In addition, the compounds are also characterized by their extremely high retention in the stratum corneum and thus expected to be applied to the treatment of onychomycosis.
However, even though the agents show high antifungal effects and high retention in the stratum corneum and they excel in actual scenes of therapeutic experiments, the effects of the agents have not reached a level expected from the results of in vitro studies.
This fact may be caused by the presence of a physicochemical factor that prevents any of those agents from reaching to a focus and effecting thereon. In other words, it is implicated that, by overcoming such an inhibitory factor by pharmaceutical countermeasures, those agents may satisfactory exert their inherent antifungal effects, thereby providing more excellent antifungal pharmaceutical compositions. As information that confirms such an implication, there is reported that, for example, crystal precipitation of lanoconazole in formulation thereof is an inhibitory effect on the penetration of the agent into the body (see, for example, Patent Document 3). In this document, even though the crystal precipitation of lanoconazole is prevented by the addition of lactic acid, the use of such an inhibitory procedure does not sufficiently prevent the crystal precipitation at the present. The causes of such crystal precipitation include: (1) the solubility of a compound represented by the general formula (1) below and/or a salt thereof to formulation components; (2) when a formulation is applied to the skin or nail, the interaction between the formulation and the surface structure of the skin or nail or the interaction between the formulation and any component such as a salt on the surface of the skin or nail; (3) the influence of vaporization or the like of a solvent; and so on, but most parts of mechanisms thereof are unknown.
The above-mentioned causes, by which expected results cannot be obtained, are thought to be phenomena specific to the compound represented by the general formula (1) and/or a salt thereof. Therefore, it is implicated that another inhibitory factor for the expression of a pharmaceutical effect is a barrier function of stratum corneum, which tends to prevent the compound from passing through the stratum corneum and reaching to a focus. In addition, it is further implicated that any of those compounds is allowed to be easily transferred into the blood after passing through the stratum corneum and the accumulation of the agent on the focus is thus inhibited, so the compound is prevented from exerting its effect. In other words, the factors that inhibit the expression of effects are complicated, so such a problem cannot be sufficiently solved at the present.
On the other hand, N-methyl-2-pyrrolidone has been known as a component capable of increasing the penetrability of an antifungal agent to stratum corneum and also considered to be used in combination with lanoconazole (see, for example Patent Document 4).
However, a formulation, in which a compound represented by the general formula (1) below and/or a salt thereof including lanoconazole is used in combination with N-methyl-2-pyrollidone, has not been known at all. In addition, in such a formulation, the compound represented by the general formula (1) below has not been known to satisfactory exert its inherent effect at all.
(where X represents a hydrogen atom or a chlorine atom)

    Patent Document 1: JP 62-93227 A    Patent Document 2: JP 10-226686 A    Patent Document 3: JP 2002-363070 A    Patent Document 4: JP 2004-529923 A